| ADAM10 endopeptidase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 3.4.24.81 | ||||||||
| CAS no. | 193099-09-1 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
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A Disintegrin and metalloproteinase domain-containing protein 10, also known as ADAM10 or CDw156 or CD156c is a protein that in humans is encoded by the ADAM10 gene. [5]
Members of the ADAM family are cell surface proteins with a unique structure, possessing both potential adhesion and protease domains. Sheddase, a generic name for the ADAM metallopeptidase, functions primarily to cleave membrane proteins at the cellular surface. Once cleaved, the sheddases release soluble ectodomains with an altered location and function. [6] [7] [8]
Although a single sheddase may “shed” a variety of substances, multiple sheddases can cleave the same substrate resulting in different consequences. This gene encodes an ADAM family member that cleaves many proteins including TNF-alpha and E-cadherin. [5]
ADAM10 (EC#: 3.4.24.81) is a sheddase, and has a broad specificity for peptide hydrolysis reactions. [9]
ADAM10 cleaves ephrin, within the ephrin/eph complex, formed between two cell surfaces. When ephrin is freed from the opposing cell, the entire ephrin/eph complex is endocytosed. This shedding in trans had not been previously shown, but may well be involved in other shedding events. [10]
In neurons, ADAM10 is the most important enzyme, with α-secretase activity for proteolytic processing of the amyloid precursor protein. [11] ADAM10, along with ADAM17, cleaves the ectodomain of the triggering receptor expressed on myeloid cells 2 (TREM2), to produce soluble TREM2 (sTREM2), which has been proposed as a CSF and sera biomarker of neurodegeneration. [12]
ADAM10 belongs to subfamily A, the most ancestral subfamily of ADAM proteins, which is shared by all major groups of animals, choanoflagellates, fungi, and green algae from the class Mamiellophyceae. [13]
Although no crystallographic x-ray diffraction analyses have been published that depict the entire structure of ADAM10, one domain has been studied using this technique. The disintegrin and cysteine-rich domain (shown to the right) plays an essential role in regulation of protease activity in vivo. Recent experimental evidence suggests that this region, which is distinct from the active site, may be responsible for substrate specificity of the enzyme. It is proposed that this domain binds to particular regions of the enzyme's substrate, allowing peptide bond hydrolysis to occur in well defined locations on certain substrate proteins. [14]
The proposed active site of ADAM10 has been identified by sequence analysis, and is identical to enzymes in the Snake Venom metalloprotein domain family. The consensus sequence for catalytically active ADAM proteins is HEXGHNLGXXHD. Structural analysis of ADAM17, which has the same active site sequence as ADAM10, suggests that the three histidines in this sequence bind a Zn2+ atom, and that the glutamate is the catalytic residue. [15]
Although the exact mechanism of ADAM10 has not been thoroughly investigated, its active site is homologous to those of well studied zinc-proteases such as carboxypeptidase A and thermolysin. Therefore, it is proposed that ADAM10 utilizes a similar mechanism as these enzymes. In zinc proteases, the key catalytic elements have been identified as a glutamate residue and a Zn2+ ion coordinated to histidine residues. [16]
The proposed mechanism begins with deprotonation of a water molecule by glutamate. The resultant hydroxide initiates a nucleophilic attack on a carbonyl carbon on the peptide backbone, producing a tetrahedral intermediate. This step is facilitated by electron withdrawal from oxygen by Zn2+ and by zinc's subsequent stabilization of the negative charge on the oxygen atom in the intermediate state. As electrons move down from the oxygen atom to re-form the double bond, the tetrahedral intermediate collapses to products with protonation of -NH by the glutamate residue. [16]
ADAM10 plays a key role in the modulation of the molecular mechanisms responsible for dendritic spine formation, maturation and stabilization and in the regulation of the molecular organization of the glutamatergic synapse. Consequently, an alteration of ADAM10 activity is strictly correlated to the onset of different types of synaptopathies, ranging from neurodevelopmental disorders, i.e. autism spectrum disorders, to neurodegenerative diseases, i.e. Alzheimer's Disease. [17]
A number of different proteins on the surface of Plasmodium falciparum malaria parasites help the invaders bind to red blood cells. But once attached to host blood cells, the parasites need to shed the 'sticky' surface proteins that would otherwise interfere with entrance into the cell. The Sheddase enzyme, specifically called PfSUB2 in this example, is required for the parasites to invade cells; without it, the parasites die. The sheddase is stored in and released from cellular compartments near the tip of the parasite, according to the study. Once on the surface, the enzyme attaches to a motor that shuttles it from front to back, liberating the sticky surface proteins. With these proteins removed, the parasite gains entrance into a red blood cell. The entire invasion lasts about 30 seconds and without this ADAM metallopeptidase, malaria would be ineffective at invading the red blood cells. [18]
In combination with low doses of herceptin, selective ADAM10 inhibitors decrease proliferation in HER2 over-expressing cell lines while inhibitors, that do not inhibit ADAM10, have no impact. These results are consistent with ADAM10 being a major determinant of HER2 shedding, the inhibition of which, may provide a novel therapeutic approach for treating breast cancer and a variety of other cancers with active HER2 signaling. [19]
The presence of the product of this gene in neuronal synapses in conjunction with protein AP2 has been seen in increased amounts in the hippocampal neurons of Alzheimer's disease patients. [20]
ADAMs are a family of single-pass transmembrane and secreted metalloendopeptidases. All ADAMs are characterized by a particular domain organization featuring a pro-domain, a metalloprotease, a disintegrin, a cysteine-rich, an epidermal-growth factor like and a transmembrane domain, as well as a C-terminal cytoplasmic tail. Nonetheless, not all human ADAMs have a functional protease domain, which indicates that their biological function mainly depends on protein–protein interactions. Those ADAMs which are active proteases are classified as sheddases because they cut off or shed extracellular portions of transmembrane proteins. For example, ADAM10 can cut off part of the HER2 receptor, thereby activating it. ADAM genes are found in animals, choanoflagellates, fungi and some groups of green algae. Most green algae and all land plants likely lost ADAM proteins.
Sheddases are membrane-bound enzymes that cleave extracellular portions of transmembrane proteins, releasing the soluble ectodomains from the cell surface. Many sheddases are members of the ADAM or aspartic protease (BACE) protein families.
A disintegrin and metalloprotease 17 (ADAM17), also called TACE, is a 70-kDa enzyme that belongs to the ADAM protein family of disintegrins and metalloproteases.
Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein (APP) in its transmembrane region. Specifically, alpha secretases cleave within the fragment that gives rise to the Alzheimer's disease-associated peptide amyloid beta when APP is instead processed by beta secretase and gamma secretase. The alpha-secretase pathway is the predominant APP processing pathway. Thus, alpha-secretase cleavage precludes amyloid beta formation and is considered to be part of the non-amyloidogenic pathway in APP processing. Alpha secretases are members of the ADAM family, which are expressed on the surfaces of cells and anchored in the cell membrane. Several such proteins, notably ADAM10, have been identified as possessing alpha-secretase activity. Upon cleavage by alpha secretases, APP releases its extracellular domain - a fragment known as APPsα - into the extracellular environment in a process known as ectodomain shedding.
A disintegrin and metalloproteinase with thrombospondin motifs 4 is an enzyme that in humans is encoded by the ADAMTS4 gene.
Disintegrin and metalloproteinase domain-containing protein 12 is an enzyme that in humans is encoded by the ADAM12 gene. ADAM12 has two splice variants: ADAM12-L, the long form, has a transmembrane region and ADAM12-S, a shorter variant, is soluble and lacks the transmembrane and cytoplasmic domains.
Disintegrin and metalloproteinase domain-containing protein 15 is an enzyme that in humans is encoded by the ADAM15 gene.
A disintegrin and metalloproteinase with thrombospondin motifs 1 is an enzyme that in humans is encoded by the ADAMTS1 gene.
Disintegrin and metalloproteinase domain-containing protein 9 is an enzyme that in humans is encoded by the ADAM9 gene.
ADAM19 , is a human gene.
Disintegrin and metalloproteinase domain-containing protein 22 also known as ADAM22 is an enzyme that in humans is encoded by the ADAM22 gene.
A disintegrin and metalloproteinase with thrombospondin motifs 8 is an enzyme that in humans is encoded by the ADAMTS8 gene.
A disintegrin and metalloproteinase with thrombospondin motifs 10 is an enzyme that in humans is encoded by the ADAMTS10 gene.
Disintegrin and metalloproteinase domain-containing protein 23 is a non-catalytic protein that in humans is encoded by the ADAM23 gene. It is a member of the ADAM family of extracellular matrix metalloproteinases.
A Disintegrin and metalloproteinase domain-containing protein 8 is an enzyme that in humans is encoded by the ADAM8 gene.
Disintegrin and metalloproteinase domain-containing protein 28 is an enzyme that in humans is encoded by the ADAM28 gene.
Disintegrin and metalloproteinase domain-containing protein 11 is an enzyme that in humans is encoded by the ADAM11 gene.
A disintegrin and metalloproteinase with thrombospondin motifs 3 is an enzyme that in humans is encoded by the ADAMTS3 gene. The protein encoded by this gene is the major procollagen II N-propeptidase.
Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.
Disintegrin and metalloproteinase domain-containing protein 20 is an enzyme that in humans is encoded by the ADAM20 gene. It is a membrane disintegrin-metalloprotease that belongs to the ADAM family. It is exclusively expressed in Testes and is similar to sperm cell-specific fertilins -alpha and -beta.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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